The Dawn of a New Era in Genetic Medicine

The field of genetic testing is relatively young but is rapidly becoming one of the most important new areas of modern medicine. It’s been over 20 years since the first human genetic code was sequenced, which took a decade of development and cost over a billion dollars. Since then, the cost of DNA sequencing has rapidly declined, and we are now learning about the genetics of human biology and its impact on disease at an accelerating pace. Two of the biggest surprises to me of the last decade of research are that 1) human genetic variation is much greater than expected, and 2) genetic disorders are both more common and complex in the human population than previously thought. Despite this complexity, enormous gains have been made. Genetic testing is beginning to play a significant role in the diagnosis and treatment of disease across virtually all areas of medicine. This includes cancer, heart disease, neurological disorders, and pediatric diseases.

Genetic variation in the human population is much greater than previously thought

Ten years ago, a clinical-grade DNA sequence for a single disease-causing gene cost as much as $3,000 (and there are approximately 20,000 genes in the genome). Today’s clinical laboratories can simultaneously sequence hundreds, and even thousands, of genes for a few hundred dollars, a fraction of the cost of just one gene a decade ago. With the decrease in cost, DNA testing is rapidly moving from basic research into clinical medicine and the race is on to look at genetics in the broader context of human disease. Soon, we will be able to sequence the entire genome at high resolution to identify all known genetic variants at a reasonable cost. (Low resolution, research-grade whole genome sequencing is already available but misses many of the most complex variant types required for clinical medicine.)

It was originally thought that there would be a “normal” healthy genome that all other genomes could be compared to and that each mutation was abnormal and might cause disease. We now know that there is tremendous genetic variation within the human population, and only a fraction of those variants cause disease. No single person’s genome can be defined as the gold standard, “normal” genome. We share most of our genetic code, but each of us is unique. There are approximately 20,000 genes that code for proteins in the human genome, and most genes contain thousands of variants across different individuals. As there are over seven billion people in the world and only a small portion have ever had their DNA sequenced, we are still in the very early stages of cataloging all of the variants and the impact they have on biology and disease.

Not only is the genome complex, it’s also “messy” with many unusual complex variant types that must be interpreted clinically. A single letter change is the most common but larger deletions, insertions, inversions, repeats, and copy number variants also represent a disproportionate share of pathogenic mutations. For example, there are estimated to be almost as many pseudogenes in the genome as functioning genes. Pseudogenes are genomic “fossils,” genes that are carried along in the genome but no longer code for functioning proteins (although they may have other functions). A mutation in a pseudogene may be mistaken for a mutation in the active gene and must be resolved to determine if the mutation is harmless or life-threatening. The most common genetic cause of death in newborns, spinal muscular atrophy, has exactly that type of problem and requires special clinical analysis.

In part, because of its complexity, genetic testing is a very misunderstood field today. Knowledge of genetics, for many consumers, has been defined by DNA tests for ancestry that sometimes provide a modest amount of health information. While consumer DNA tests can help inform us of our ancestry, they are not always useful for understanding medical conditions. The majority of consumer DNA tests look at a relatively small number of simple common variants (such as three well-characterized BRCA mutations for breast cancer that are found almost exclusively in the Ashkenazi Jewish population). Unfortunately, some of the most common genetic disorders also have a high prevalence of very complex, difficult to sequence variants (pseudogenes are just one example) that require much more sophisticated sequencing and analysis techniques. One can think of the typical consumer genetic test as a very low resolution scan of Earth from high altitude that shows where cities are located. Clinical genetic tests, then, correlate to a very high resolution Google street map with all of the detail included. While consumer DNA tests can be informative at times and can find some common simple variants causing disease, they miss the vast majority of variants that are clinically important to medical diagnosis and treatment. Fortunately, as costs have come down, high-resolution clinical tests are now available for a few hundred dollars from multiple clinical labs that are comparable to the cost of a consumer genetic test.

Genetics is personal

In the late 1990s my oldest sister’s newborn granddaughter was diagnosed with a rare genetic disease called galactosemia. Galactosemia is caused when both copies of a gene involved in metabolizing galactose (a common sugar found in many foods) are defective. If you inherit one faulty gene, you will still produce enough of the enzyme made by the gene to function normally. If you inherit two bad copies, the disease can be extremely severe. Within days to weeks, the child may have severe and permanent intellectual disability. Some children die within the first months of life. Fortunately my grandniece was diagnosed promptly and the treatment is straightforward: galactose must be eliminated from the diet for life. For me, it was the first realization that virtually all individuals and all families carry risk for genetic conditions. I, too, carry the gene for galactosemia, as do some of my children. But now we know it is important to do carrier screening in advance to be prepared for these types of recessive disorders.

A number of years later, my nephew died of a sudden heart attack at the age of 27. It turns out that he had a genetic mutation for hypertrophic cardiomyopathy—a common cause of sudden cardiac death in young people. Because he was adopted, no one knew about his family history, which later revealed a long family trend toward early cardiac events. My sister now shares her story of loss in her role as an advocate for genetic testing.

Historically genetic testing was expensive and, therefore, restricted to patients who had serious symptoms or had a significant family history of a genetic condition. Now that genetic testing costs are coming down, we are seeing a slow shift toward more proactive genetic testing. Family history is often inaccurate or unknown and thus not that reliable. In the future we will be able to screen for many genetic events long before they happen—and hopefully alleviate enormous human suffering from unexpected genetic conditions.

What good is a genetic diagnosis if you can’t do anything about it?

Enormous progress is being made in developing therapeutics for genetic diseases, and hope is rapidly emerging everywhere. New technologies for gene therapy and gene editing as well as the development of traditional therapies targeting specific genetic disorders bring new hope that, perhaps, no disease is incurable.

For example, epilepsy is the most frequent chronic neurologic condition in children. About half of cases are caused by genetic mutations, and an increasing number of those cases have potential therapies. There are over 100 different genes involved in epilepsy. All can now be tested simultaneously at very high resolution for a few hundred dollars.

CLN2 deficiency is one such rare epilepsy disorder. Seizures are one of the first symptoms, but the disease quickly moves into a more serious neurological disorder. Children with CLN2 deficiency are often completely normal for the first 2-3 years of life but then begin to develop seizures followed by the loss of neuromuscular function. Most children don’t survive to their teenage years. Imagine your healthy, loving, two year old beginning to lose all function, and there is nothing you can do. Except, now you can! A drug for CLN2 deficiency is available that stops the progression of the disease, but only if the disease is diagnosed promptly at the onset of symptoms.